Viraemia control after cessation of therapy
With many patients on potent HAART regimens maintaining detectable but stable viral loads, it is increasingly important to understand the dynamics of viral evolution occurring at these low levels to ensure that viral control is maintained over the long term. A number of studies explained the phenomena of viral suppression through virus characteristics, mutational changes at low-levels of viremia and evolution after partial treatment interruptions (PTI).
An international collaboration between Swiss, US and UK researchers examined the viral characteristics responsible for spontaneous control of plasma viremia by analysing in vitro infectivity, growth kinetics, co-receptor usage, genetic subtype and env diversity by RT-PCR cloning and phylogenetic analysis.
Twenty chronically infected patients from the Swiss Spanish Intermittent Therapy Trial (SSITT) who had undertaken four cycles of treatment interruptions, two weeks off and eight weeks on therapy followed by a long interruption were grouped according to spontaneous control of plasma viral load (VL) between weeks 40 and 76. The researchers found that patients who controlled viraemia upon STI treatment had a significantly lower in vitro replication capacity (RC) and low RC was also strongly correlated with low pre-HAART VL levels. In vitro techniques confirmed that viral growth rates strongly correlated with levels of infectivity. Control of viremia after STI was strongly correlated to lower viral load levels before initiation of antiretroviral treatment.
The analysis of intra-patient env diversity revealed that patients who controlled viraemia after STIs had significantly lower viral diversity before initiating treatment. These findings suggest that low level replicating virus may have been present before HAART was initiated, and not as a result of STI. Co-receptor usage and genetic subtypes did not differ between the two patient groups, although patients controlling viremia showed higher neutralisation activity. This study shows that in this group of patients undergoing STI treatment, both in vitro RC and infectivity predicts control of plasma viraemia (Gunthard).
Viral evolution following partial treatment interruption
Following on from previous presentations on the impact of partial treatment interruptions (PTI) where one class of treatment may be interrupted rather than a complete regimen, Steve Deeks from University of California, San Francisco described the evolution of viral populations after PTI. Twenty five patients with >90% adherence, persistent viraemia >400 copies and detectable PI levels underwent PTI, 19 patients interrupting PI therapy and 6 interrupting RTI therapy.
Wild type (WT) virus did not emerge during PTI and patients who interrupted PIs observed no loss of PI mutations during weeks 16 to 24. Given the history of RTI use in the pre-HAART era, archived virus may have been expected to emerge, but was not present during this period. Under phylogenetic analysis one patient was considered to have PI susceptible virus after week 36, explained by escape of an archived virus
The authors attribute loss of resistance to increasing levels of RC and higher levels of virus in most patients. They conclude therefore that PI interruption in patients with treatment experience and multi-drug resistant virus is associated with stable virus levels but no loss in PI resistance. One explanation that they provide for this finding is that viral evolution in the presence of PI treatment is associated with the accumulation of compensatory mutations that lead to an increase in viral fitness. An early decrease in viral fitness achieved by PI treatment may prevent future viral reversion (Deeks).
References
Deeks SG et al. Limited genotypic and phenotypic evolution after interruption of a single therapeutic drug class in patients with multidrug resistant HIV. Antiviral Therapy 8: S73, 2003.
Gunthard H et al. Virus characteristics predict viraemia control after cessation of antiretroviral therapy. Antiviral Therapy 8: S63, 2003.